Pravastatin alleviates interleukin 1β-induced cartilage degradation by restoring impaired autophagy associated with MAPK pathway inhibition


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Abstract

BackgroundOsteoarthritis (OA) is a chronic degenerative joint disease characterized by cartilage degradation driven by proinflammatory cytokines; meanwhile, statins display anti-inflammatory effects. Here we assessed the effects of pravastatin on inflammatory rat chondrocytes and explored the underlying mechanism.MethodsRat articular chondrocytes were pretreated with pravastatin and subsequently stimulated with IL-1β. Then, the expression levels of OA- and autophagy-related effectors, at the mRNA and protein levels, were examined by real-time polymerase chain reaction (RT-PCR) and Western blotting, respectively. Autophagic flux in chondrocytes in different treatment groups was monitored via GFP-mRFP-LC3 adenovirus transfection and confocal microscopy. Activation of MAPK, PI3K/Akt, and NF-κB pathways in chondrocytes with or without pravastatin treatment during IL-1β stimulation was examined by Western blotting.ResultsOur results showed that pravastatin downregulated the degradation related genes MMP3, MMP13 and ADAMTS5, as well as extracellular matrix degeneration induced by IL-1β. In addition, pravastatin upregulated the autophagy related genes atg7, atg12, Beclin1, and LC3 II in IL-1β stimulated chondrocytes. GFP-mRFP-LC3 adenovirus transfection also indicated that pravastatin restored impaired autophagy in OA chondrocytes. Furthermore, we demonstrated that regulation of the MAPK signaling pathway may be responsible for autophagy regulation in the articular cartilage.ConclusionsTaken together, these findings suggested that pravastatin restores impaired autophagic flux by inhibiting MAPK activation and protects the cartilage against inflammatory responses, suggesting a potential role for autophagic flux in pravastatin-mediated cartilage protection.HighlightsPravastatin protects rat articular chondrocytes from IL-1β-induced degradation.Pravastatin restores impaired autophagic activity in IL-1β-stimulated chondrocytes.Pravastatin inhibits MAPK signaling pathway activation by IL-1β.

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